DESCRIPTION (adapted from abstract) During the previous grant period, the PI demonstrated that 1,25 dihydroxyvitamin D3 (1,25D) induces typical morphologic, biochemical and molecular features of apoptosis in MCF-7 human breast cancer cells. The overall hypothesis is the 1,25D and its nuclear receptor, the vitamin D receptor (VDR) coordinately regulate mammary epithelial cell proliferation and apoptosis. This renewal application will investigate 1,25D signaling in relation to proliferation and apoptosis of normal and transformed mammary epithelial cells. Three specific aims will be addressed concurrently: 1. Characterized downstream signaling from VDR leading to apoptosis in MCF-7 cells and a vitamin D resistant variant. 2. Examine transcriptional regulation of the human VDR promoter in mammary cells, and to provide evidence of a role for VDR in mammary gland function in vivo. These three diverse specific aims will comprehensively examine the role of 1,25D and the VDR in regulation of proliferation and apoptosis of mammary epithelial cells using cellular, molecular and whole animal approaches.